Trajectories of gut microbiota and nonatopic wheeze: an early-life microbial footprint on preschool asthma

Extract

In recent years, the early-life gut microbiome has gained significant attention as a potentially modifiable determinant of childhood asthma [1–3]. This interest has been driven largely by epidemiological studies linking gut microbial composition and maturation during infancy to asthma development later in life. However, efforts to identify specific microbial signatures that are causally linked to asthma have faced challenges due to disease heterogeneity, timing of exposures and host–environment interactions [4]. In this issue of ERJ Open Research, a new analysis from the Canadian Healthy Infant Longitudinal Development (CHILD) cohort study contributes to this growing body of research by identifying distinct gut microbiota trajectories in infancy that are linked to nonatopic preschool asthma (defined as wheeze) by age 5 years [5]. This work provides new insight into an under-studied but prevalent phenotype of preschool asthma.

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Early-life gut microbial trajectories are associated with nonatopic preschool asthma and are possibly modified by breastfeeding practices https://bit.ly/4jNAPgI

In recent years, the early-life gut microbiome has gained significant attention as a potentially modifiable determinant of childhood asthma [1–3]. This interest has been driven largely by epidemiological studies linking gut microbial composition and maturation during infancy to asthma development later in life. However, efforts to identify specific microbial signatures that are causally linked to asthma have faced challenges due to disease heterogeneity, timing of exposures and host–environment interactions [4]. In this issue of ERJ Open Research, a new analysis from the Canadian Healthy Infant Longitudinal Development (CHILD) cohort study contributes to this growing body of research by identifying distinct gut microbiota trajectories in infancy that are linked to nonatopic preschool asthma (defined as wheeze) by age 5 years [5]. This work provides new insight into an under-studied but prevalent phenotype of preschool asthma.

Building on early theories such as the hygiene hypothesis, which proposed that reduced microbial exposure in infancy increases susceptibility to allergic diseases like asthma, subsequent research has explored how the gut microbiome may shape immune development [6]. The concept that the infant gut microbiome influences asthma risk evolved through high-resolution molecular studies [7]. The Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) cohorts have been instrumental in establishing links between delayed microbiota maturation and later asthma, especially in children of asthmatic mothers [4]. Specifically, children with low microbiota-by-age at 1 year were shown to be more likely to develop asthma by age 5 years, and this association was mediated by depletion of beneficial taxa such as Faecalibacterium, Bifidobacterium and Roseburia[4]. These taxa need to be tested as possible biomarkers of microbial maturation and immune tolerance.

Another critical dimension, the diet–microbiome interactions, is being investigated in childhood asthma. In 9-year-olds from inner-city environments, specific gut microbiota clusters and whole-food dietary patterns were associated with asthma severity. A Prevotella-dominated network was notably depleted in allergic asthma with low lung function [8]. Importantly, children with low Clostridia-rich networks who ate processed diets had a higher asthma burden, suggesting that diet may enhance or mitigate microbiota-related risk [4]. A literature review from our group reinforced that it is not just the gut microbiota composition but the interaction between gut and airway microbiota that influences asthma development [9]. Environmental exposures (e.g. farming and exposure to air pollution) and host immune-metabolic responses in predisposed hosts (e.g. children with a history of hospitalisation with a severe respiratory infection) increase the asthma diagnosis risk [9]. The important point is that the timing of colonisation matters. For example, early-life microbiome perturbation may have an impact on regulatory pathways, particularly those involving short-chain fatty acid and amino acid metabolism, and mucosal immunity. To this end, our group has shown that nasopharyngeal microbiota profiles during a severe bronchiolitis episode dominated by Haemophilus influenzae were significantly associated with increased severity [10, 11]. In addition, infants with a nasopharyngeal profile characterised by a high abundance of H. influenzae, a predominance of rhinovirus (RV)-A and RV-C infections, and elevated asthma genetic risk, had a significantly higher risk of developing asthma (35.9% versus 16.7%; adjusted OR 2.24, 95% CI 1.02–4.97; p=0.046) [11].

The new study from the CHILD cohort focused on nonatopic preschool asthma, a distinct phenotype of wheezing illness in childhood. Starting with 3264 children, to end with 1203 children included in the statistical analysis, Moore et al. [5] used clustering methods on 16S rRNA data to classify gut microbiota at 3 and 12 months into four trajectories. The trajectory of patients with gut microbiome profiles characterised by low to high Bacteroides levels was significantly associated with increased odds of nonatopic preschool asthma (OR=1.74) compared to the trajectory of patients with gut microbiome profiles characterised by consistently high Bacteroides levels. Conversely, the trajectory of patients with consistently high Bacteroides levels was protective (OR=0.52) against nonatopic preschool asthma development. Furthermore, children with high faecal secretory IgA levels at 3 months and with the low to high Bacteroides levels trajectory had higher odds of nonatopic wheeze, especially if not exclusively breastfed (OR=4.10), when compared with the group of children who had low secretory lgA levels. This analytical approach offered a deeper insight to the asthma–microbiome interactions by showing that we need to test the dynamic shifts of gut microbiome composition over time, rather than reporting associations between single time-points and asthma development. The use of longitudinal microbiota trajectories offers a framework of understanding of disease progression rather than focusing on cross-sectional snapshots.

The study by Moore et al. [5] is a large cohort study with longitudinal data. The investigators performed rigorous 16S sequencing and trajectory-based clustering using capturing significant associations. By integrating immune markers (i.e. faecal secretory IgA) and looking into breastfeeding as a possible effect modifier, Moore et al. [5] also explored further interaction effects. Another important point is that they focused on nonatopic preschool asthma, a phenotype that is under-investigated. However, similar to all excellent observational studies, this one also has weaknesses. Despite adjusting for known confounders (e.g. maternal asthma and smoking), unmeasured variables such as recurrent severe respiratory viral infections or exposure to indoor pollutants may influence both microbiota composition and preschool asthma development. In addition, the observed associations do not imply causation. Importantly, reverse causality (e.g. early airway inflammation altering gut microbiota via the gut–lung axis) cannot be excluded. Functional insights are also missing. Future integration of metagenomics or metabolomics could more strongly support the immunomodulatory potential of these microbiome trajectories. Finally, the lack of virome data may also impair the interpretation of the findings. External validation in other cohorts, possibly with an inferred geographic diversity, will further support the findings of this study.

The findings of this study by Moore et al. [5] align with emerging insights that the timing and trajectory of gut microbiota development influence immune outcomes. However, better understanding of the underlying mechanisms will guide better personalised medicine approaches. For example, by integrating genomics and microbiome data in longitudinal trajectories, we will be able to understand whether, in genetically susceptible hosts, there would be a benefit of microbiome modulation. In addition, understanding the impact of breastfeeding more in depth will support advocacy measures that aim to increase breastfeeding rates in the community. Lastly, but very importantly, the impact of personalised dietary interventions in the prevention of preschool asthma is crucial.

To summarise, the study by Moore et al. [5] adds a compelling chapter to the evolving quest around the gut microbiome–asthma association. By showing that gut microbial trajectories in infancy are associated with nonatopic preschool asthma, it underscores the importance of longitudinal microbiome cohorts over time, not just cross-sectional perspectives (see suggested speculative figure 1). This is a study that highlights the need for targeted, timed and multifaceted interventions to modulate immune development early in life in ways that may ultimately reduce the burden of asthma.

FIGURE 1.

Interaction between early-life gut microbiome trajectories, faecal secretory IgA and breastfeeding, in relation to nonatopic preschool asthma risk: the odds of developing nonatopic preschool asthma based on combinations of early-life gut microbiota trajectories, faecal secretory IgA levels at 3 months and breastfeeding status. a) The study by Moore et al. [5] showed the highest risk was observed among infants with low Bacteroides abundance at 3 months, high faecal secretory IgA levels, and who were partially or not breastfed. In contrast, b) reduced Bacteroides abundance with lower secretory IgA levels, c) other microbiota trajectories (reference group; OR=1) and d) exclusive breastfeeding were associated with lower odds of wheeze. This emphasises the potential immune-modifying role of maternal IgA from exclusive breastfeeding in mitigating asthma risk, despite endogenous secretory IgA production.